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Establishment and Characterization of Three Afatinib-resistant Lung Adenocarcinoma PC-9 Cell Lines Developed with Increasing Doses of Afatinib
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Establishment and Characterization of Three Afatinib-resistant Lung Adenocarcinoma PC-9 Cell Lines Developed with Increasing Doses of Afatinib

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Afatinib prolongs survival compared with gefitinib in an epidermal growth factor receptor-driven lung cancer model

Takashi Ninomiya1, Nagio Takigawa, Eiki Ichihara

  • 1Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.

Molecular Cancer Therapeutics
|February 28, 2013
PubMed

Insights

Afatinib, an irreversible ErbB family blocker, demonstrated superior efficacy over gefitinib in inhibiting EGFR-mutated lung tumors and overcoming resistance. Combination therapy with bevacizumab further enhanced tumor suppression, particularly in T790M-mutated models.

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • Activating epidermal growth factor receptor (EGFR) mutations drive tumor growth in certain cancers.
  • Reversible EGFR tyrosine kinase inhibitors (TKIs) face challenges with acquired resistance, including the T790M mutation.
  • Irreversible ErbB family blockers offer a potential strategy to overcome resistance and enhance treatment efficacy.

Purpose of the Study:

  • To compare the efficacy of afatinib, an irreversible ErbB blocker, with gefitinib, a reversible EGFR TKI, in preclinical models of EGFR-mutated lung cancer.
  • To evaluate afatinib's ability to overcome acquired resistance associated with the T790M mutation.
  • To assess the therapeutic potential of combining afatinib with bevacizumab.

Main Methods:

  • Transgenic mice with EGFR exon 19 deletion mutations were treated with afatinib, gefitinib, or vehicle.
  • Tumor burden was assessed, and molecular analyses (immunoblotting) were performed to evaluate drug effects on signaling pathways and apoptosis.
  • Survival studies and xenograft models with specific EGFR mutations (exon 19 deletion/T790M and L858R/T790M) were utilized.

Main Results:

  • Afatinib significantly reduced tumor multiplicity compared to vehicle and showed a trend towards greater reduction than gefitinib.
  • Afatinib demonstrated broader target suppression (pEGFR, pHER2) and prolonged apoptosis induction compared to gefitinib.
  • Afatinib significantly improved mouse survival and, in combination with bevacizumab, showed superior efficacy against xenograft tumors harboring T790M mutations.

Conclusions:

  • Afatinib exhibits greater potency than gefitinib in EGFR exon 19 deletion-mutated tumors.
  • Afatinib effectively suppresses tumors with the T790M resistance mutation, both as a single agent and in combination with bevacizumab.
  • The findings support afatinib's role as a potent therapeutic option for EGFR-mutated lung cancers, including those with acquired resistance.

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